System with photonic biopsy device for obtaining pathological information

ABSTRACT

A biopsy device includes a tubular member, a hollow shaft and an elongated fiber body having at least one optical fiber. The hollow shaft has a laterally (sidewardly) facing notch in its distal portion. The tubular member is movable relative to the shaft, between a first position in which the notch is covered by the tubular member, and a second position in which the notch is not covered by the tubular member. The shaft is movable between a first position in which the distal end of the optical fiber is located at the distal end of the shaft with the elongated fiber body extending through the notch, and a second position in which the distal end of the at least one optical fiber is located proximally to the notch.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application is the U.S. National Phase application under 35 U.S.C.§ 371 of International Application Serial No. PCT/IB2013/059712, filedon Oct. 28, 2013, which claims the benefit of U.S. application Ser. No.61/721,541, filed on Nov. 2, 2012. These applications are herebyincorporated by reference herein.

FIELD OF THE INVENTION

The invention generally relates to a system including facilities forin-vivo and for ex-vivo tissue inspection. Particularly, the inventionrelates to a system including a biopsy device with optical fibers and alateral notch for in-vivo tissue inspection and for taking a biopsywhich may additionally be subjected to ex-vivo tissue inspection.

BACKGROUND OF THE INVENTION

Traditional pathology makes use of ex-vivo analysed tissue samples. As aresult some of the relevant information of the in-vivo tissue state,e.g. its metabolic state, is lost in this process and cannot be measuredon the tissue slide used for histopathology diagnostics. Biopsies aretypically performed by surgeons or interventional radiologists, andsubsequently examined by a pathologist. An exemplary workflow forobtaining a biopsy is depicted in FIG. 1. For positioning the biopsydevice (usually a needle with a shaft 100 having a lateral recess 200,and an outer tubular member 500) accurately in the suspicious tissue,the correct location is commonly determined using image guidance such asUltrasound or X-ray. While imaging may provide coarse guidance of theneedle towards the region of interest, it is often challenging toprecisely identify the boundaries of small lesions or tumors with thebiopsy needle using standard imaging modalities. As a consequence,biopsies are often taken at the wrong location, which increases the riskof false diagnoses. An additional challenge is the heterogeneity presentin many tumors where for example multiple biopsies in different regionsof the tumor are required, and this requires more accurate positioningin different parts of the tumor tissue. The association between biopsylocation and subsequent biopsy histopathology analysis is important toassess the heterogeneity and the optimal (targeted) therapy to choose.This is becoming more important with the increasing use of neoadjuvantcancer therapy, prior to surgery, e.g. in breast cancer.

There are various imaging devices that provide in-vivo information suchas functional MRI imaging and PET-CT imaging. Due to the above describeddifficulties, it is difficult to link information obtained by theseimaging modalities to histopathology results from a biopsy slide takenfrom the body because the link to the exact position of the biopsy isdifficult, in part because of limited resolution of the imagingmodalities.

In order to position a biopsy needle under image guidance moreaccurately in the suspicious tissue, tissue sensing at the tip of thedevice may be required. Current biopsy needles often do not have suchtissue feedback possibilities. Recently, elongated interventionaldevices have been reported with optical fibers integrated into thedevice which provide feedback from the tissue at the tip of the device.Such devices allow for fine-guidance towards small volumes of suspicioustissue, in particular for tissue which does not show sufficient contrastin imaging. In order to allow tissue discrimination, these devicesemploy diffuse reflectance spectroscopy (DRS). For DRS, such devicesshould be designed with the maximum possible distance between the sourceand detector fibers to ensure an optimal tissue characterization.

SUMMARY OF THE INVENTION

Whereas tissue sensing at the tip can ensure that the device iscorrectly positioned at the location of interest, it is desirable thatthe biopsy is obtained from exactly the same location. For this, aspecial design is required to ensure that the correct tissue sample iscaptured in the notch of a biopsy device. During tissue measurements,the notch of the biopsy device is at a different location than theposition of the fiber ends at the tip of the device. A specialconstruction is required such that when the biopsy is taken after thetissue sensing is completed, the notch of the biopsy device ispositioned at the location where the final tissue sensing took place.

For biopsy devices with a lateral notch, the presence of the notch setsstrict constraints for integrating the optical fibers within the device.Consequently, the fibers would be confined to the lower part of theshaft of the device, resulting in a small and likely insufficientsource-detector fiber distance at the tip.

A biopsy device may consist of several moveable parts, which in the caseof a fully-automated biopsy gun are ejected at high speeds with abruptmovements. Accordingly, the optical fibers need to be integrated in away which ensures their mechanical stability and which does not restrictthe usability of the biopsy gun.

Further, the typical workflow for obtaining a biopsy should not bechanged.

It may be seen as an object to integrate optical fibers at the tip of abiopsy device (needle) in such a way that (1) the obtained tissue sample(biopsy) is the same as the tissue investigated by optical fibers priorto taking the biopsy, (2) a sufficient source-detector fiber distancecan be realized for tissue characterization, and (3) that themodifications do not require a change in the clinical workflow of astandard biopsy procedure. It may be seen as a further object to combinein-vivo information, for example metabolic information to the standardhistopathology to obtain an advanced pathology data set, integratingconventional pathology staining results with such information on anindividual cellular level, and to provide more complete information onthe biological characteristics and behaviour of the cells, relevant forimproved diagnostics (including therapy response monitoring).

In other words: it is an object of the invention to provide system andmethod for obtaining in-vivo and ex-vivo pathological information of asingle tissue sample, i.e. the same tissue sample. This and furtherobjects are solved by the subject-matter of the independent claim.Further embodiments are described in the dependent claims.

The invention proposes an integrated solution for adding tissue sensingat the tip of a biopsy device. The biopsy device consists of the opticalsensing part at the tip of the device and a shaft with a lateral notchcharacterized in that the position of optical sensing part before takingthe biopsy and the proximal position of the notch when taking the biopsyare substantially the same. Hence when the shaft is pushed forward (asin FIG. 3B) the notch will fill with tissue that had been sensed in FIG.3A.

Generally, a system according to an embodiment may comprise a biopsydevice with a tubular member, a hollow shaft and an elongated fiberbody. The hollow shaft may have a distal end and a shaft portionadjacent the distal end, wherein a laterally (sidewardly) facing notchis formed in that portion of the shaft. The elongated fiber body mayinclude at least one optical fiber, preferably at least two opticalfibers, with a distal end.

The fiber body may be movably accommodated within the hollow shaft, andthe shaft may be movably accommodated within the tubular member, whereinthe tubular member is movable between a first position in which thenotch is covered by the tubular member, and a second position in whichthe notch is not covered by the tubular member, and wherein the fiberbody is movable between a first position in which the distal end of theoptical fiber is located at the distal end of the shaft with theelongated fiber body extending through the notch, and a second positionin which the distal end of the at least one optical fiber is locatedproximally to the notch.

Accordingly, the shaft of a biopsy device is formed as a hollow shaftthat provides space for inserting an elongated body with integratedoptical fibers. During device (needle) positioning, the full volume ofthe shaft, including the notch, is now occupied by the fiber body andallows for guiding the optical fibers to the tip with a sufficientlylarge source-detector fiber distance to ensure an accurate tissuecharacterization.

When the biopsy is taken, the fiber body is released from the shaft andthe full volume of the notch becomes available for securing the biopsy.Thus, the use within the clinical workflow remains essentially the sameas for a conventional biopsy needle, except the added tissue sensingfunctionality during needle positioning.

According to an embodiment, the fiber body comprises a bevel at a distalend of the fiber body, wherein the distal end of the at least oneoptical fiber is located at the bevel of the fiber body, wherein asmooth surface is formed by the front surface of the optical fiber andthe surface of the bevel. Alternatively, the distal end of the at leastone optical fiber may protrude beyond the bevel of the fiber body.Alternatively, the distal end of at least one optical fiber may belocated inside the fiber body adjacent the bevel. Furthermore, the frontsurface of the optical fiber may have a different angle than the bevelof the fiber body.

A ‘bevel’ is a geometrical structure allowing for introducing the needleinto tissue. Usually, a shaft of a needle includes a circular crosssection. The distal end of a needle shaft is cut such that an ovalsurface is formed, which is inclined relative to the longitudinal axisof the shaft. The bevel forms a pointed tip at the most distal end ofthe needle. It should be noted that the bevel might form an acute anglewith the shaft, such that the needle includes a pointed tip. Preferably,the acute angle might be approximately 20°.

According to an embodiment, the bevel of the fiber body together withthe slanted surface of the distal end of the hollow shaft may form thegeometrical structure allowing for introduction of the device intotissue.

In the following, geometrical aspects will be defined for a betterunderstanding. First of all, the device includes a longitudinal mainaxis, usually the centre axis of a rotationally symmetrical shaft.Further, the tip portion of the device is cut at an angle to the mainaxis forming the bevel. The pointed tip of the bevel is directed to the‘front’ of the needle. As a result, looking from the ‘side’, it ispossible to recognize the angle between the bevel and the main axis, andfurther it is possible to look onto and into a recess formed at theside, i.e. laterally.

It should be noted that the end surface of a fiber at the opening in thebevel may have a circular shape or an oval shape in case of asubstantially circular cross section of the fiber. Depending on theangle at which the fiber will end at the bevel surface, the shape of theend surface of the fiber will be effected and therefore also thedirection of the emitted or received light.

The fiber body has an outer diameter, and the end surfaces of the fibersare arranged within the body at a distance to each other. Preferably,the distance between the fiber ends is greater than the diameter of thebody. For example, the distance is more than 1.1 times greater than thediameter. Particularly, the distance may be more than 1.25 times greaterthan the diameter. Preferably, the distance may be more than 1.5 timesgreater than the diameter. In other words, the distance between thefiber ends should be as great as possible. Such distances are measuredfrom the central axis of one of the fibers to the central axis of theother one of the fibers.

It will be understood that the tubular member may include a sharpeneddistal edge.

According to a further embodiment, an insert may be arranged within thehollow shaft between the distal end of the hollow shaft and the notch,wherein the insert may include openings for accommodating the distal endof the at least one optical fiber, when the fiber body is in the firstposition, i.e. when the fiber body is in a position in which the distalend of the optical fiber(s) is located at the distal end of the shaftwith the elongated fiber body extending through the notch.

According to another embodiment, the biopsy device may further comprisea channel for injecting or extracting a fluid. Such a channel may be anadditional channel formed in the fiber body and extending through thatbody in a longitudinal direction, but may also be formed in the wall ofthe shaft or between the fiber body and the shaft or between the shaftand the outer tubular member.

According to a further embodiment, the biopsy device may furthercomprise a tissue retraction channel, wherein a suction device may applyvacuum to the channel for retracting a sample of tissue. For example,the channel in which the fiber body is accommodated within the shaft,may be used for retracting a sample, after removing the fiber body.Alternatively, the channel may be formed in the fiber body betweenoptical fibers which are preferably arranged as much as possible atopposite sides of the elongated body.

According to another embodiment, the biopsy device further comprises aconsole including a light source, a light detector and a processing unitfor processing the signals provided by the light detector, wherein oneof the light source and the light detector may provide wavelengthselectivity. The light source may be one of a laser, a light-emittingdiode or a filtered light source, and the console may further compriseone of a fiber switch, a beam splitter or a dichroic beam combiner.Furthermore, the device may be adapted to perform at least one out ofthe group consisting of diffuse reflectance spectroscopy, diffuseoptical tomography, differential path length spectroscopy, and Ramanspectroscopy.

The system may further comprise a device adapted for ex-vivo tissueinspection, and/or a storage container for receiving an extracted tissuesample and for storing pathology information obtained by an in-vivotissue inspection and/or an ex-vivo tissue inspection.

According to another aspect, a method for obtaining pathologicalinformation regarding a tissue sample is provided, the method generallycomprising the steps of obtaining information from an in-vivo tissueinspection, obtaining information from an ex-vivo tissue inspection,wherein the same tissue sample is inspected firstly in-vivo and thenex-vivo.

The in-vivo tissue inspection may include at least one out of the groupconsisting of diffuse reflectance spectroscopy, diffuse opticaltomography, differential path length spectroscopy, and Ramanspectroscopy. On the other hand, the ex-vivo tissue inspection mayinclude at least one of making tissue slices, staining by Hematoxylinand eosin (H&E) and/or a specific biomarker, and optically scanning.

According to an embodiment, the method may further comprise the step ofintegrating the information obtained by in-vivo tissue inspection andthe information obtained by ex-vivo tissue inspection. For example, thein-vivo obtained information may be used for an interpretation of theex-vivo obtained information.

The method may further comprise the step of storing the pathologyinformation of the tissue sample, obtained by the in-vivo tissueinspection and/or by the ex-vivo tissue inspection, by a storagecontaining which may also be adapted to receive a tissue sample.

The aspects defined above and further aspects, features and advantagesof the present invention may also be derived from the examples ofembodiments to be described hereinafter and are explained with referenceto examples of embodiments. The invention will be described in moredetail hereinafter with reference to examples of embodiments but towhich the invention is not limited.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of taking a biopsy with a known needle.

FIG. 2 shows a biopsy device according to a first embodiment.

FIG. 3 illustrates steps of taking a biopsy with a device of FIG. 2.

FIG. 4 shows a biopsy device according to a second embodiment.

FIG. 5 illustrates steps of taking a biopsy with a device of FIG. 4.

FIG. 6 shows a system including a biopsy device and a console.

FIG. 7 shows a log plot of absorption coefficient of blood, water andfat.

FIG. 8 shows fluorescence curves for collagen, elastin, NADH and FAD.

FIG. 9 is a flow chart illustrating steps of a method according to anembodiment.

The illustration in the drawings is schematically only and not to scale.It is noted that similar elements are provided with the same referencesigns in different figures, if appropriate.

DETAILED DESCRIPTION OF EMBODIMENTS

In FIG. 2, a first embodiment of a biopsy device is shown, having ahollow shaft 10, fiber body 35 and an outer tubular member 50. Thehollow shaft 10 includes a distal end or tip 15 forming a slantedsurface, wherein the slanted surface may have an oval shape in case thehollow shaft has a circular cross section. Furthermore, a lateral recessor notch 20 is formed in the shaft, wherein the notch 20 issubstantially formed by a lateral opening and a section of the boreextending through the shaft in a longitudinal direction.

The fiber body 35 is formed by an elongated and solid element in whichchannels for accommodating optical fibers 40 are provided. The fiberbody includes a bevel 30 at the distal end thereof. The outer tubularmember 50 comprises a sharpened distal edge.

For a better visualization, the fiber body is in FIG. 2 in anintermediate position with the bevel 30 within the notch 20.

For tissue sensing, an optical fiber 40 for illumination and collectinglight is required with distal end at the tip 15 of the biopsy device.The proximal end of the fiber may be connected to an optical consolecapable of sending and receiving light.

For optimal tissue sensing, it is required to guide at least two opticalfibers 40 (source and detector) towards the device tip 15, and the fibertip ends should have a maximized distance from each other. According tothe first embodiment, this is achieved by a hollow shaft providing spacefor inserting a fiber body 35 with optical fibers 40 integrated at asufficient source-detector fiber distance at the tip, i.e. at the bevel30.

In a typical clinical workflow shown in steps A-C of FIG. 3, the biopsydevice is inserted into the patient with the outer tubular member 50(the cutting cannula) covering the notch 20 of the shaft 10 to ensure asmooth protrusion (step A in FIG. 3). Hence the notch 20 is not exposedto the tissue in this step, and the hollow space in the shaft 10(including the notch 20) can be occupied by the fiber body withoutaltering the workflow. The proposed solution allows for additionaltissue characterization at the tip during needle positioning.

At the target location, the shaft 10 is ejected whereas the fiber body35 remains in its position (step B in FIG. 3). Thereby, the notch 20 isno longer occupied by the tubular member 50 and the biopsy can beobtained in a conventional way (step C in FIG. 3).

Whereas the hollow shaft 10 and the tubular member 50 are moveableparts, the fiber body may remain at a fixed position during the entireprocedure. Since the fiber body 35 with the integrated optical fibers 40is not moved, the design is compatible with fast (fully-automated)shooting mechanisms, where the workflow steps B and C are successivelyexecuted at high speed. Thus, the risk of damaging the optical fibers 40by strong mechanical forces can be circumvented.

The length and position of the shaft 10 may be chosen in such a way thatthe fiber body 35 is facing the proximal side of the notch 20 whenexposed after the ejection (step B). This allows for a directcharacterization of the tissue present in the notch 20, just before thebiopsy is taken (step C). With this option, a confirmation measurementfrom the tissue in the notch can be performed in-situ, and an optimalcorrelation between the biopsy sample and the optical measurement can beensured. This is particularly useful for biopsy devices with a manual orsemi-automated shooting mechanism, where the workflow steps 2 and 3 canbe executed with a user-defined time delay to allow for additionaltissue measurements in the notch.

FIG. 4 shows a second embodiment of a biopsy device which differs fromthe first embodiment (FIG. 2) in that an insert 12 is inserted in theportion of the hollow shaft 10 between the distal end 15 and the notch20. The insert 12 may be a small fixed element at the tip by means ofwhich the tip of the hollow shaft 10 may be closed during biopsy. For abetter visualization, the fiber body 35 is in FIG. 4 in an intermediateposition with the protruding ends of the optical fibers 40 within thenotch 20.

Similar to steps A-C of FIG. 3, steps A-C of FIG. 5 show a clinicalworkflow where the biopsy device shown in FIG. 4 is inserted into thepatient with the outer tubular member 50 (the cutting cannula) coveringthe notch 20 of the shaft 10 (step A in FIG. 5). During ejection of theshaft 10, tissue may enter the hollow tip portion of the shaft and maybe cut by the protruding shaft with the hole (step B in FIG. 5). Aninsert 12 may ensure that the amount of tissue being cut is only theabsolute minimum that is medically required for obtaining a properbiopsy. As in step C of FIG. 3, biopsy can be obtained as shown in stepC in FIG. 5.

The insert 12 has two or more (conical) openings/channels 13 which arejust large enough (typically some 100 μm) for loosely guiding theoptical fibers 40 towards the tip 15 of the shaft 10. The fiber body 35is adapted accordingly, so that the optical fibers 40 protrude awell-defined extent out of the body to fit into the guiding channels 13of the insert 12. Preferably, the dimensions of the insert are minimized(some millimetres only) to reduce the required protrusion length of theoptical fibers 40 from the body of the fiber body 35.

Furthermore, a small opening for applying vacuum can be realized withinthe shaft or in the fiber body, and it may be used for sucking tissueinto the notch 20 after the shaft 10 has been ejected (step B) to ensurethat the biopsy is of sufficient size. By way of this, the underpressuremay ensure that the tissue is brought in close contact with the opticalfibers 40 facing the proximal side of the exposed notch 20, for the casethat the tissue in the notch is characterized prior to obtaining thebiopsy.

Such an opening 45 is schematically illustrated in FIG. 2, wherein thisopening may be formed within the shaft 10, within the fiber body 35, butalso as a gap between the shaft 10 and the fiber body 35.

The incorporation of a small opening for applying underpressure can alsoallow for simultaneous biological/physiological analysis of theblood/tissue under consideration, thus obtaining a better biopsyquality. The underpressure can be used to suck in small amounts(microliter) of body fluid (for instance blood/serum, bile, or else) forinstant biochemical analysis, which can be used to complement theoptical tissue characterization.

For this, the underpressure is preferably realized by a small vacuumopening within the fiber body, so that the blood sampling can beperformed within the described design at the tip (workflow step A inFIG. 3) and also in the notch (step B in FIG. 3). The absorbedblood/cells could be analyzed by appropriate detectors (such aschip-sized microfluidic devices and/or MEMS) connected to the distal endof the vacuum channel, thereby enabling instantaneous analysis.

For instance, MEMS-based pH sensors could allow for complementaryclassification of tumor (acidic) vs. normal (basic) tissue based on pH.Apart from pH sensors, also other specific sensors may be used thatcould characterize the tissue sample in consideration. This could serveas complimentary means to support the optical tissue sensing indifficult cases, and thereby improve the results of photonic biopsyprocedures even further.

It is noted that the ‘bevel’ might also have another shape or structureat the tip of the device, useful for introducing the device into atissue. For example, the bevel might be a convex or concave surface, orthe bevel might be a combination of several small surfaces, whereinthese surfaces are connected to each other by steps or edges. It mightalso be possible that the cross section of the shaft is not completelycut by the bevel, such that an area remains which is blunt, i.e. is forexample perpendicularly orientated relative to the longitudinal axis ofthe shaft. Such a ‘blunt’ end might include rounded edges or might alsoform a rounded leading edge. As another example, a sharp edge might beformed by two or more slanted surfaces being symmetrically orasymmetrically arranged to form the tip of the device.

As shown in FIG. 6, the fibers 40 of the interventional device areconnected to an optical console 60. The optical fibers can be understoodas light guides or optical waveguides. In an embodiment, the console 60comprises a light source 64 in the form of a halogen broadband lightsource with an embedded shutter, and an optical detector 66. The opticaldetector 66 can resolve light with a wavelength substantially in thevisible and infrared regions of the wavelength spectrum, such as from400 nm to 1700 nm. The combination of light source 64 and detector 66allows for diffuse reflectance measurements. For a detailed discussionon diffuse reflectance measurements see R. Nachabe, B. H. W. Hendriks,A. E. Desjardins, M. van der Voort, M. B. van der Mark, and H. J. C. M.Sterenborg, “Estimation of lipid and water concentrations in scatteringmedia with diffuse optical spectroscopy from 900 to 1600 nm”, J. Biomed.Opt. 15, 037015 (2010).

Optionally it is also possible that the console is couple to an imagingmodality capable of imaging the interior of the body, for instance whenthe biopsy is taken under image guidance. In this case it is alsopossible to store the image of the interior when the biopsy is taken toa container of the biopsy. In this case the in-vivo information of theoptical biopsy needle, the information of the pathology of the biopsy aswell as the location where the biopsy was taken are brought together foradvanced pathology.

On the other hand, also other optical methods can be envisioned likediffuse optical tomography by employing a plurality of optical fibers,differential path length spectroscopy, fluorescence and Ramanspectroscopy to extract tissue properties.

Further shown in FIG. 6 are a suction device 70, a device 80 forobtaining ex-vivo pathology information, and a storage container 90. Thesuction device may be connected to a proximal end of the biopsy device,such that underpressure or a vacuum can be applied through the biopsydevice to the distal end of the same, in particular to the notch at thedistal end of the biopsy device.

The device 80 may be connected to the console 60 by means of a wire orwireless, for interchanging information like control commands or datarepresenting pathological aspects of an inspected tissue sample. Thedevice 80 may be a digital pathology systems consisting of an opticalscanner and an image management system to enable digitizing, storage,retrieval, and processing of tissue staining images, reading theinformation stored in the storage box container, and integrating thisinformation with the digitized staining data set, to be presented to thepathologist. In addition to this, the data set from the photonic biopsydevice may be either presented next to the histopathology image or thetwo data sets may be fused in the image, characterized and recognizableby a certain coloring pattern of the image. For instance the oxygenationlevel measured in-vivo could be added as a red color, where deep redmeans low oxygenation and bright red would mean high oxygenation level.Additionally, molecular spatial distributions from FTIR or Raman couldbe added as a color coded mapping to the pathology slide of specificmolecules.

The tissue sample, which may firstly be subjected to an in-vivo tissueinspection, i.e. an inspection within a living body, and which maysecondly subjected to an ex-vivo tissue inspection by means of thedevice 80, may be situated in the container 90. Molecular diagnosticscan also be performed on the tissue biopsy (e.g. sequencing or PCR), orpart of the biopsy.

The storage container for the biopsy may further be such that theoptical information obtained in-vivo and/or ex-vivo can be stored on it.This can be a barcode label which can be read at the pathologydepartment by the digital pathology device. It can also be a micro chipwhere the optical information can be stored electronically. Instead ofstoring the actual information it is also possible to store an “address”or “link” of where the information may be retrieved.

According to another embodiment, the container 90 may be placed in theconsole 60. The data can then be written on the container while thephotonic biopsy device is attached to the console. The data can bewritten in the form of a barcode or can electronically be stored in thechip on the container.

A processor transforms the measured spectrum into physiologicalparameters that are indicative for the tissue state and a monitor 68 maybe used to visualize the results.

A computer program executable on the processor may be provided on asuitable medium such as an optical storage medium or a solid-statemedium supplied together with or as part of the processor, but may alsobe distributed in other forms, such as via the Internet or other wiredor wireless telecommunication systems.

For fluorescence measurements the console must be capable of providingexcitation light to at least one source fiber while detectingtissue-generated fluorescence through one or more detection fibers. Theexcitation light source may be a laser (e.g. a semiconductor laser), alight-emitting diode (LED) or a filtered light source, such as afiltered mercury lamp. In general, the wavelengths emitted by theexcitation light source are shorter than the range of wavelengths of thefluorescence that is to be detected. It is preferable to filter out theexcitation light using a detection filter in order to avoid possibleoverload of the detector by the excitation light. A wavelength-selectivedetector, e.g. a spectrometer, is required when multiple fluorescententities are present that need to be distinguished from each other.

In case fluorescence measurements are to be combined with diffusereflectance measurements, the excitation light for measuringfluorescence may be provided to the same source fiber as the light fordiffuse reflectance. This may be accomplished by, e.g., using a fiberswitch, or a beam splitter or dichroic beam combiner with focusingoptics. Alternatively, separate fibers may be used for providingfluorescence excitation light and light for diffuse reflectancemeasurements.

To perform spectroscopy, the acquired spectra may be fitted using acustom made Matlab 7.9.0 (Mathworks, Natick, Mass.) algorithm. In thisalgorithm, a widely accepted analytical model was implemented, namelythe model introduced by the reference T. J. Farrel, M. S. Patterson andB. C. Wilson, “A diffusion theory model of spatially resolved,steady-state diffuse reflectance for the non-invasive determination oftissue optical properties”, Med. Phys. 19 (1992) p. 879-888, which ishereby incorporated by reference in entirety. The input arguments forthe model of this reference are the absorption coefficient μ_(a) (λ),the reduced scattering coefficient μ′_(s) (λ) and the center-to-centerdistance between the emitting and collecting fibers at the tip of theprobe.

In the following part, the model will be explained briefly. The usedformulas are mainly based on work of Nachabe et al., and reference isthus made to R. Nachabe, B. H. W. Hendriks, M. van der Voort, A. E., andH. J. C. M. Sterenborg “Estimation of biological chromophores usingdiffuse optical spectroscopy: benefit of extending the UV-VIS wavelengthrange to include 1000 to 1600 nm”, Optics Express, vol. 18, 2010, pp.1432-1442, which is hereby incorporated by reference in entirety, andfurthermore reference is made to R. Nachabe, B. H. W. Hendriks, A. E.Desjardins, M. van der Voort, M. B. van der Mark, and H. J. C. M.Sterenborg, “Estimation of lipid and water concentrations in scatteringmedia with diffuse optical spectroscopy from 900 to 1600 nm”, J. Biomed.Opt. 15, 037015 (2010), which is also hereby incorporated by referencein entirety.

A double power law function can be used to describe the wavelengthdependence of the reduced scattering, where the wavelength A isexpressed in nm and is normalized to a wavelength value of λ=800 nm. Theparameter a corresponds to the reduced scattering amplitude at thisspecific wavelength.

$\begin{matrix}{{\mu_{s}(\lambda)} = {{\alpha\left( {{\rho_{MR}\left( \frac{\lambda}{\lambda_{0}} \right)}^{- b} + {\left( {1 - \rho_{MR}} \right)\left( \frac{\lambda}{\lambda_{0}} \right)^{- 4}}} \right)}\mspace{14mu}\left\lbrack {cm}^{- 1} \right\rbrack}} & \left( {{Eq}.\mspace{14mu} 1} \right)\end{matrix}$

In this equation the reduced scattering coefficient is expressed as thesum of Mie and Rayleigh scattering where ρ_(MR) is the Mie-to-totalreduced scattering fraction. The reduced scattering slope of the Miescattering is denoted b and is related to the particle size. For ahomogeneous distribution of absorbers, the total light absorptioncoefficient μ_(a) (λ) can be computed as products of the extinctioncoefficients and volume fraction of the absorbers (see FIG. 8)μ_(a) ^(Total) =f ₁μ_(a) ¹ +f ₂μ_(a) ² +f ₃μ_(a) ³+  (Eq. 2)

Instead of modeling the absorption coefficient μ_(a) (λ) as the sum ofabsorption coefficients weighted by the respective concentrations of thefour chromophores of interest, it was decided to express the tissueabsorption coefficient asμ_(a) ^(Tissue)(λ)=C(λ)ν_(Blood)μ_(a) ^(Blood)(λ)+ν_(WL)μ_(a) ^(WL)(λ)[cm⁻¹]  (Eq. 3)

where μ_(a) ^(Blood)(λ) corresponds to the absorption by blood and μ_(a)^(WL)(λ) corresponds to absorption by water and lipid together in theprobed volume. The volume fraction of water and lipid isν_(wL)=[Lipid]+[H₂O], whereas ν_(Blood) represents the blood volumefraction for a concentration of hemoglobin in whole blood of 150 mg/ml.

The factor C is a wavelength dependent correction factor that accountsfor the effect of pigment packaging and alters for the shape of theabsorption spectrum. This effect can be explained by the fact that bloodin tissue is confined to a very small fraction of the overall volume,namely blood vessels. Red blood cells near the center of the vesseltherefore absorb less light than those at the periphery. Effectively,when distributed homogeneously within the tissue, fewer red blood cellswould produce the same absorption as the actual number of red bloodcells distributed in discrete vessels. The correction factor can bedescribed as

$\begin{matrix}{{C(\lambda)} = \frac{1 - {\exp\left( {{- 2}\; R\;{\mu_{a}^{Blood}(\lambda)}} \right)}}{2\; R\;{\mu_{a}^{Blood}(\lambda)}}} & \left( {{Eq}.\mspace{14mu} 4} \right)\end{matrix}$

where R denotes the average vessel radius expressed in cm. Theabsorption coefficient related to blood is given byμ_(a) ^(Blood)(λ)=α_(BL)μ_(a) ^(HbO) ² (λ)+(1−α_(BL))μ_(a) ^(Hb)(λ)[cm⁻¹]  (Eq. 5)

where μ_(a) ^(HbO) ² (λ) and μ_(a) ^(Hb) (λ) represent the basicextinction coefficient spectra of oxygenated hemoglobin HbO₂ anddeoxygenated hemoglobin Hb, respectively. The oxygenated hemoglobinfraction in the total amount of hemoglobin is noted α_(BL),=[HbO₂]/([HbO₂]+[Hb]) and is commonly known as the blood oxygensaturation. The absorption due to the presence of water and lipid in themeasured tissue is defined asμ_(a) ^(WL)(λ)=α_(WL)μ_(a) ^(Lipid)(λ)+(1−α_(WL))μ_(a) ^(H) ² ^(O)(λ)[cm⁻¹]  (Eq. 6)

In this case the concentration of lipid related to the totalconcentration of lipid and water together can be written asα_(WF)=[Lipid]/([Lipid]+[H₂O]), where [Lipid] and [H₂O] correspond tothe concentration of lipid (density of 0.86 g/ml) and water,respectively.

This way of relating the water and lipid parameters in the expression ofthe absorption coefficient defined in Eq. 6, rather than estimatingseparately the water and lipid volume fraction corresponds to aminimization of the covariance of the basic functions for fittingresulting in a more stable fit cf. the reference R. Nachabe, B. H. W.Hendriks, M. van der Voort, A. E., and H. J. C. M. Sterenborg“Estimation of biological chromophores using diffuse opticalspectroscopy: benefit of extending the UV-VIS wavelength range toinclude 1000 to 1600 nm”, Optics Express, vol. 18, 2010, pp. 1432-1442.For further explanation and validation of this theorem reference is madeto the reference R. Nachabe, B. H. W. Hendriks, A. E. Desjardins, M. vander Voort, M. B. van der Mark, and H. J. C. M. Sterenborg, “Estimationof lipid and water concentrations in scattering media with diffuseoptical spectroscopy from 900 to 1600 nm”, J. Biomed. Opt. 15, 037015(2010).

For example by means of the described algorithm optical tissueproperties may be derived such as the scattering coefficient andabsorption coefficient of different tissue chromophores: e.g.hemoglobin, oxygenated haemoglobin, water, fat etc. These properties aredifferent between normal healthy tissue and diseased (cancerous) tissue.

The main absorbing constituents in normal tissue dominating theabsorption in the visible and near-infrared range are blood (i.e.hemoglobin), water and fat. In FIG. 8 the absorption coefficient ofthese chromophores as a function of the wavelength are presented. Notethat blood dominates the absorption in the visible range, while waterand fat dominate in the near infrared range.

The total absorption coefficient is a linear combination of theabsorption coefficients of for instance blood, water and fat (hence foreach component the value of that shown in FIG. 7 multiplied by itsvolume fraction). By fitting the model to the measurement while usingthe power law for scattering, the volume fractions of the blood, waterand fat as well as the scattering coefficient may be determined.

Another way to discriminate differences in spectra is by making use of aprincipal components analysis. This method allows classification ofdifferences in spectra and thus allows discrimination between tissues.Apart from diffuse reflectance also fluorescence may be measured. Thenfor instance parameters like collagen, elastin, NADH and FAD could bemeasured too (see FIG. 8). Especially, the ratio NADH/FAD, which iscalled the optical redox parameter, is of interest because it is anindicator for the metabolic state of the tissue, as described in ZhangQ., et al. “Turbidity-free fluorescence spectroscopy of biologicaltissue”, Opt. Lett., 2000 25(19), p. 1451-1453, which is changed incancer cells and assumed to change upon effective treatment of cancercells.

It is also possible to detect the response of the body to exogenousfluorophores that can be detected by the optical biopsy device.Furthermore, these could also be linked to measurements of the exogenousfluorophores by imaging modalities like optical mammography based ondiffuse optical imaging.

The described devices can be used in minimally invasive needleinterventions such as low-back pain interventions or taking biopsies inthe field of cancer diagnosis or in case where tissue characterizationaround the needle is required.

In the following, exemplary needle devices will be described withrespect to their outer diameter, their insertion length, and theirpreferred use.

A biopsy needle might have an outer diameter of 1.27 mm up to 2.108 mm,might be inserted into tissue with 100 mm to 150 mm of its length, andmight be used in soft tissue core biopsies in the neck, the head, thebreast, the prostate, and the liver.

A fine aspiration needle of soft tissue might have an outer diameterbetween 0.711 mm and 2.108 mm, might be inserted into soft tissue with100 mm to 150 mm of its length, and might be used for aspiration of softtissue.

A brain biopsy needle might have an outer diameter of 2.108 mm, might beinserted into tissue with 150 mm up to 250 mm of its length, and mightbe used for diagnostic brain biopsies.

Finally, the device may include a needle electrode having an outerdiameter of 2.108 mm and smaller, the electrode might be inserted intotissue up to 250 mm of its length, and might be used for radiofrequencyablation for instance of tumors.

The flow-chart in FIG. 9 illustrates the principle of the stepsperformed in accordance with an embodiment described herein. It will beunderstood that the steps described, are major steps, wherein thesemajor steps might be differentiated or divided into several sub-steps.Furthermore, there might be also sub-steps between these major steps. Instep S1, a photonic biopsy device is positioned within tissue of aliving body. This may be performed under image guidance. Furthermore,the positioning may be controlled by means of the tissue inspectionprovided by the optical fibers within the biopsy device.

In step S2, when a target region for a biopsy is reached, an in-vivotissue inspection is performed to obtain in-vivo information related toa specific tissue.

In step S3, the inspected tissue is extracted from the living body. Theextraction may take place either by removing the biopsy device with thetissue sample sealed in the notch of the device, or by applying vacuumand sucking out the tissue sample through a channel provided in thebiopsy device. The extracted tissue sample may then be transferred to adevice for ex-vivo tissue inspection.

It is noted that sucking out the tissue sample and thus leaving the tipof the biopsy device in the target region may provide for thepossibility to perform the method again in close vicinity to the formertissue inspection, if necessary. This may be decided immediately afterextracting and ex-vivo inspecting the former tissue sample.

In step S4, an ex-vivo tissue inspection is performed on the previouslyextracted tissue sample. The step may include any necessary preparationsteps like making tissue slices and staining the slices with H&E and/orwith specific biomarkers. The tissue slices may also be digitized usinga digital pathology system.

In step S5, the information obtained in-vivo is combined and/orintegrated with the information obtained ex-vivo. This can also bemolecular diagnostics data (e.g. sequencing or PCR), performed on thetissue biopsy or part of the biopsy.

In step S6, the tissue sample may be situated in a storage container tosave the sample. Together with the tissue, all the obtained informationmay be stored at the container, for example in an electronic chip,wherein the information may include the in-vivo pathology data, theex-vivo pathology data, the information representing the location atwhich the biopsy has been taken, and the like. In other words, all datareceived during the complete method, may be stored together with thesample in the storage container.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive; theinvention is not limited to the disclosed embodiments. Other variationsto the disclosed embodiments may be understood and effected by thoseskilled in the art in practicing the claimed invention, from a study ofthe drawings, the disclosure, and the appended claims.

In the claims, the word “comprising” does not exclude other elements orsteps, and the indefinite article “a” or “an” does not exclude aplurality. The mere fact that certain measures are recited in mutuallydifferent dependent claims does not indicate that a combination of thesemeasured cannot be used to advantage. Any reference signs in the claimsshould not be construed as limiting the scope.

LIST OF REFERENCE SIGNS

-   10 shaft-   12 insert-   13 opening-   15 distal end-   20 recess-   30 bevel-   35 fiber body-   40 optical fiber-   40 channel/opening-   45 tubular member-   50 distal edge-   55 console-   64 light source-   66 light detector-   68 monitor-   70 suction device-   80 device for ex-vivo tissue inspection-   90 storage container-   100 shaft-   200 notch-   500 outer member

The invention claimed is:
 1. A method for obtaining pathologicalinformation regarding a tissue sample of a tissue using a biopsy devicecomprising a tubular member, a hollow shaft having a distal end, thehollow shaft having a sidewardly facing notch adjacent the distal end ofthe hollow shaft, wherein the hollow shaft is movably accommodatedwithin the tubular member, and an elongated fiber body including atleast one optical fiber, the at least one optical fiber having a distalend, wherein the fiber body is accommodated within the hollow shaft, themethod comprising acts of: positioning the at least one optical fiber ata distal tip of the distal end of the hollow shaft; performing in-vivotissue inspection by positioning the biopsy device within the tissue;obtaining information from the in-vivo tissue inspection; obtaining thetissue sample using the biopsy device by keeping the elongated fiberbody at a same position adjacent to the tissue sample while initiallymoving the hollow shaft from a first position in which the sidewardlyfacing notch is covered by the tubular member and the distal end of theat least one optical fiber is located at a distal tip of the distal endof the hollow shaft with the elongated fiber body extending through thesidewardly facing notch, to a second position in which the notch is notcovered by the tubular member and the distal end of the at least oneoptical fiber is located proximally to the sidewardly facing notch, andthen moving the tubular member to a location in which the sidewardlyfacing notch is covered by the tubular member; performing ex-vivo tissueinspection on the tissue sample obtained using the biopsy device;obtaining information from the act of performing the ex-vivo tissueinspection using a tissue analyzer, wherein the same tissue sample issubjected to the in-vivo tissue inspection and to the ex-vivo tissueinspection.
 2. The method of claim 1, wherein the in-vivo tissueinspection includes at least one out of the group consisting of diffusereflectance spectroscopy, fluorescence spectroscopy, diffuse opticaltomography, differential path length spectroscopy, and Ramanspectroscopy.
 3. The method of claim 1, wherein the ex-vivo tissueinspection includes at least one of making tissue slices, staining byHematoxylin and eosin and/or a specific biomarker, and opticallyscanning.
 4. The method of claim 1, further comprising an act ofintegrating the information obtained by the in-vivo tissue inspectionand the information obtained by the ex-vivo tissue inspection.
 5. Themethod of claim 1, further comprising an act of storing the pathologicalinformation of the tissue sample in a memory of a storage containerwhich is further configured to receive the tissue sample.